Reviewing the current evidence supporting early B-cells as the cellular origin of Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a highly malignant skin cancer characterized by early metastases and poor survival. Although MCC is a rare malignancy, its incidence is rapidly increasing in the U.S. and Europe. The discovery of the Merkel cell polyomavirus (MCPyV) has enormously impacted our understanding of its etiopathogenesis and biology. MCCs are characterized by trilinear differentiation, comprising the expression of neuroendocrine, epithelial and B-lymphoid lineage markers. To date, it is generally accepted that the initial assumption of MCC originating from Merkel cells (MCs) is unlikely. This is owed to their post-mitotic character, absence of MCPyV in MCs and discrepant protein expression pattern in comparison to MCC. Evidence from mouse models suggests that epidermal/dermal stem cells might be of cellular origin in MCC. The recently formulated hypothesis of MCC originating from early B-cells is based on morphology, the consistent expression of early B-cell lineage markers and the finding of clonal immunoglobulin chain rearrangement in MCC cells. In this review we elaborate on the cellular ancestry of MCC, the identification of which could pave the way for novel and more effective therapeutic regimens.

Merkel cell carcinoma

“…Initially, the favoured theory was that MCC originates from Merkel cells, which was followed by the hypothesis that a Merkel cell precursor, for example epidermal or dermal stem cells, is the possible cell of origin of MCC 34 . Later, the hypothesis that MCC derives from pro-B cells or pre-B cells was suggested 33,143 , based on the observation that early B cell antigens are expressed in MCC. However, to date, expression of the MCPyV T antigens has not been able to transform any of these cells in vitro .…”

Absence of immunoglobulin heavy chain rearrangement in primary Merkel cell carcinomas

“…Evidence from animal models suggests that epidermal/dermal stem cells might be the cellular origin of MCC. The recently formulated hypothesis of MCC originating from pro/pre‐B or pre‐B cells is supported by cell morphology, the consistent expression of early B‐cell lineage markers and the finding of clonal immunoglobulin chain rearrangement in MCC cells . Murakami et al .…”

“…During the past decade, evidence has been accumulating that Merkel cells, which are located at the epidermal–dermal junction, are possibly not the origin of Merkel cell carcinoma (MCC), a relatively rare but highly aggressive skin tumour . In 2013, Zur Hausen et al .…”

“…They found that one MCC had monoclonal immunoglobulin heavy chain (IgH) and immunoglobulin kappa light chain (IgK) rearrangement, while two other MCCs had IgK rearrangement . As coexpression of TdT and PAX5 is normally restricted to pro/pre‐ and pre‐B cells, the authors suggested that the cells of origin of MCC are pro/pre‐B or pre‐B cells rather than postmitotic Merkel cells . We aimed to assess the frequency of IgH rearrangement in primary MCC.…”

“…It is widely accepted that the previous hypothesis of MCC originating from Merkel cells is probably incorrect because of the postmitotic character, absence of MCPyV association and different protein expression patterns in Merkel cells compared with MCC . Evidence from animal models suggests that epidermal/dermal stem cells might be the cellular origin of MCC.…”